The elderly are challenged with a number of risk factors that predispose them to severe respiratory tract infections. Principal among these is the inability to generate protective immunity following vaccination against influenza. This is due, in part, to decreased function of the naive CD4+ T cell compartment. This proposal outlines experiments designed to ask whether vaccines that incorporate CpG, and other toll-like receptor (TLR) ligands, can be used to meaningfully boost the aged naive CD4+ T cell response. This will be determined based upon whether vaccinating with antigen plus CpG restores both the aged naive CD4+ T cell effector response (Aim 1) and the development of subsequent memory (Aim 2). In order to directly compare the young and aged naive CD4+ T cell response we will remove this population from both young and aged D4+ T cell transgenic donors and adoptively transfer these cells to normal young recipients. These mice will then be immunized with the cognate antigen with or without CpG and the transgenic response can be followed using a congenic marker. Most importantly, by infecting with a recombinant influenza virus that expresses the cognate transgenic antigen we can assess the ability of young and aged effector or memory CD4+ T cells to protect from viral infection following vaccination with or without CpG. Lastly, to determine the feasibility of this approach in aged recipients we will ask whether aged dendritic cells are activated by CpG, and other TLR ligands, to enhance antigen specific naive CD4+ T cell responses (AIM 3). [unreadable] [unreadable]